Systematic screening for new histone marks and studying their epigenetic function

表观遗传调控对不同的生物过程和疾病至关重要。翻译后 组蛋白中的修饰（PTM）通常被认为是一组主要的表观遗传标记， 有助于决定不同DNA模板生物输出的表观遗传程序。我们的团队已被 最近鉴定了九种新型组蛋白PTM（赖氨酸丙酰化、赖氨酸丁酰化、赖氨酸 丙二酰化，赖氨酸琥珀酰化，赖氨酸戊二酰化，赖氨酸巴豆酰化，赖氨酸2-羟基异丁酰化， 赖氨酸3-羟基丁酰化和赖氨酸苯甲酰化）。重要的是，我们和其他人证明了 通过揭示它们在基因转录调控中的独特功能， 表达和细胞调节，并通过将它们与多种先天性代谢疾病联系起来。其中一些 组蛋白标记物可以被其相应的短链脂质的细胞水平刺激，因此表明 代谢调节表观遗传变化的新机制。这个应用程序是基于巨大的 我们在早期研究中获得了对九种新型 组蛋白标记。我们假设，在哺乳动物中存在其他未描述类型的组蛋白PTM。 组蛋白我们的假设得到了初步数据的支持，这些数据确定了多种未描述的PTM， 组蛋白，其化学结构要么不确定，要么仍有待充分验证。我们建议 使用综合方法，采用在 我们团队的实验室，全面筛选新型组蛋白PTM。我们队是最好的 我们能够找到这些组蛋白标记是因为我们拥有巨大的技能和众多的技术， 积累，以及我们在最近鉴定的新型 组蛋白标记。我们将首先全面筛选新类型的组蛋白标记，并通过两种方法验证它们。 化学和生物化学方法。然后，我们将调查他们的表观遗传作用在精子发生。 新型的组蛋白标记将大大促进我们对染色质结构和功能的理解， 这可能会为表观遗传学研究开辟不可预见的途径，甚至可能将目前研究的重点转移到 表观遗传机制和疾病。

Epigenetic regulation is critical to diverse biological processes and diseases. Post-translational modifications (PTMs) in histones are generally considered to be a major group of epigenetic marks, contributing to the epigenetic program that dictates diverse DNA-templated biological outputs. Our team has recently identified nine types of novel histone PTMs (lysine propionylation, lysine butyrylation, lysine malonylation, lysine succinylation, lysine glutarylation, lysine crotonylation, lysine 2-hydroxyisobutyrylation, lysine 3-hydroxybutyrylation, and lysine benzoylation). Importantly, we and others demonstrated critical roles for these new PTM pathways by revealing their unique functions in the transcriptional control of gene expression and cellular regulation, and by linking them to multiple inborn metabolic diseases. Some of these histone marks can be stimulated by cellular levels of their corresponding short-chain lipids, thus suggesting new mechanisms for metabolism-regulated epigenetic changes. This application is based on the tremendous expertise we gained during our earlier studies on identification and characterization of nine novel types of histone marks. We hypothesize that additional, undescribed types of histone PTMs are present in mammalian histones. Our hypothesis is supported by our preliminary data identifying multiple undescribed PTMs in histones, the chemical structures of which are either undefined or remain to be fully validated. We propose to use an integrated approach, employing technologies that have been well established and fully validated in the laboratories of our team, to comprehensively screen for novel types of histone PTMs. Our team is best positioned to find these histone marks because of the tremendous skills and numerous technologies we have accumulated, and the high productivity we have demonstrated in our recent identification of the novel types of histone marks. We will first comprehensively screen for new types of histone marks and validate them by both chemical and biochemical methods. We will then investigate their epigenetic roles during spermatogenesis. New types of histone marks will significantly advance our understanding of chromatin structure and function, might open unforeseen avenues for epigenetic studies, and may even shift the focus of current research on epigenetic mechanisms and disease.